Project Summary Aging and the chronic diseases associated with aging place a tremendous burden on our healthcare system and reduce quality of life for the elderly. As our world population ages dramatically over the next three decades, the burden will only increase. Hence, there is a great need to discover fundamental mechanisms of aging to develop rationale strategies for minimizing the impact of aging on our health and economy. This fostered the Geroscience hypothesis, which posits that therapeutically targeting fundamental mechanisms of aging will yield a larger dividend in terms of improving the health of an aging population than would treating individual age-related diseases. The fundamental mechanism of aging where this has borne out most successfully to date is through elimination of senescent cells. Senolytic drugs were first described by us and others in 2015 and have already fostered multiple clinical trials beginning in 2018. In mice, senolytics improve physical function, tissue health and suppress all cause mortality. COVID-19 has emerged as an urgent threat to our aged population. The goal of the parent project is to fully define the mechanism by which an aged / senescent immune system drives morbidity and mortality using mice as a model organism. The goal of this revision is to use the knowledge and resources we have to study the role of cellular senescence in driving adverse outcomes in aged organisms acutely exposed to novel viral pathogens. Preliminary data indicate that mice with a substantial senescent cell burden respond much worse to inflammatory challenges than mice without senescent cells. Furthermore, exposure to normal pathogens carried by wild or pet store mice is sufficient to kill old experimental mice housed in specified pathogen-free conditions, but it does not kill young mice. Here, we propose to use this experimental paradigm to determine if senolytics, drugs that specifically kill senescent cells, suppress mortality in aged, obese, diabetic or diseased mice. The immediate goal of this revision is to generate sufficient preclinical data to support clinical trials using nutraceuticals with senolytic activity to prevent adverse outcomes in those at high risk of COVID-19 infection or grave illness after infection. The long term goal of this project is to enable rigorously testing the Geroscience hypothesis.